DE69631881T2 - PULMONAL ADMINISTRATION OF MEDICINES IN AEROSOL FORM - Google Patents

Abstract

The invention provides a spray-dried pharmaceutical-based dispersible dry powder composition for pulmonary delivery, comprising: a therapeutically effective amount of a macromolecule; and a pharmaceutically acceptable carrier with the provisos that: (i) the carrier is neither hydroxypropylcellulose or hydroxypropylmethylcellulose; and (ii) the macromolecule is neither insulin nor an interferon.

Description

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention enters generally methods and compositions for dry powder formulation of drugs, including Macromolecules for pulmonary administration.

about the years, certain drugs are sold in compositions which are suitable for forming a drug dispersion for oral inhalation (pulmonary administration) to various conditions to treat in humans. Such drug compositions for pulmonary administration are designed so that they are supplied or administered by inhalation of a drug dispersion by the patient so that the active drug in the dispersion can reach the lungs. It has been found that certain Medicines that are delivered to the lungs easily through the Alveolar region to be absorbed directly into the bloodstream. pulmonary Administration is particularly promising for the supply of macromolecules (proteins, Polypeptides and nucleic acids), which is difficult about to administer other routes of administration are. Such pulmonary administration or delivery can be used both for systemic feed for as well local feed be effective in treating lung diseases.

Pulmonary drug delivery can be achieved by various approaches, including liquid nebulizers, Dose inhalers aerosol-based (MDI) and dry powder dispersion devices. Aerosol-based MDIs lose their preference because they are based on the Use of chlorofluorocarbons (CFC) are based on which their adverse effects on the ozone layer are prohibited. Dry powder dispersion devices, which are not based on CFC aerosol technology are promising for the feeder of drugs that are easily formulated as dry powder can. Many otherwise labile macromolecules can be stable as lyophilized or spray dried Powder stored as such or in combination with suitable powder carriers become. The ability to feed However, pharmaceutical compositions as dry powder is problematic in certain respects. The dose of many pharmaceutical Compositions are common critical, so it is necessary that a dry powder feed system or dry powder delivery system is able to be precise, precise and reliably the to supply the intended amount of medicine. In addition, many are pharmaceutical Compositions very expensive. Therefore, the ability to dry powder effectively with a minimal loss of medication, critical. It is also essential that the powder be easily dispersible is prior to inhalation by the patient to ensure adequate distribution and ensure systemic absorption.

A particularly promising one Approach for uses pulmonary administration of a dry powder drug a hand device with a hand pump for providing a Compressed gas source. The compressed gas is suddenly passed through a powder dispersion device, like a venturi, released and the dispersed powder for inhalation of the patient available made. Although beneficial in many ways, there are Handheld devices are problematic with a variety of others Aspects. The fed Particles are less than 10 microns in size, usually in the range of 1 μm up to 5 μm, making powder handling and dispersion more difficult than with larger particles. The problems are exacerbated through the relatively small volumes of pressurized gas that are used hand operated pumps available are. Venturi dispersion devices are particularly unsuitable for difficult Powders to be dispersed if only small volumes of compressed gas are available. Another requirement for Hand and other powder delivery devices is efficiency. It is important that the concentration of drugs in the Gas bolus is relatively high to the number of breaths that are required is to reduce the total dose. The ability to achieve both adequate dispersion and small dispersed Volumes is an essential technical challenge that Individual requires that each unit dose of the powder composition easy and reliable is dispersible. powdery Compositions comprising inhalation macromolecules are described in WO 91/16038 and EP-A-611567.

SUMMARY OF THE INVENTION

According to the present invention, there are provided dispersible drug-based dry powder compositions, including methods of making them and dry powder dispersing devices. A dispersible drug-based composition is one that has a moisture content of less than about 10 weight percent (weight percent) water, usually less than about 5 weight percent, and preferably less than about 3 weight percent; a particle size of about 1.0 to 5.0 µm mean mass diameter (MMD), usually 1.0 to 4.0 µm MMD, and preferably 1.0 to 3.0 µm MMD; an administered dose of about> 30%, usually> 40%, preferably> 50% and most preferably> 60%; and has an aerosol particle size distribution of about 1.0 to 5.0 μm mean aerodynamic mass diameter (MMAD), usually 1.5 to 4.5 μm MMAD and preferably 1.5 to 4.0 μm MMAD. Such compositions are of pharmaceutical grade purity.

DESCRIPTION SPECIFIC EMBODIMENTS

The present invention is based at least in part on the dispersibility characteristics of the dry powder compositions drug-based, according to the present Invention are made. The dispersibility characteristics of the present drug-based compositions mean that they are more suitable for use in pulmonary delivery devices are as compositions made by other processes are. The compositions of the invention are easily aerosolized and are easily absorbed through a host's lungs when fed through a dry powder inhaler.

DEFINITIONS

When interpreting the claims of Various aspects of this invention exist in several important ways Definitions that should be considered.

The term "dispersibility" or "dispersible" means a dry powder with one Moisture content of less than about 10 weight percent (wt%) water, usually below about 5% by weight and preferably less than about 3% by weight; a particle size of about 1.0 to 5.0 μm medium mass diameter (MMD), usually 1.0 to 4.0 μm MMD, and preferably 1.0 to 3.0 µm MMD; a fed or administered dose of about> 30%, usually> 40%, preferably> 50% and most preferably> 60%; an aerosol particle size distribution from about 1.0 to 5.0 μm mean aerodynamic mass diameter (MMAD), usually 1.5 to 4.5 μm MMAD and preferably 1.5 to 4.0 μm MMAD.

The term "powder" means a composition that consists of finely dispersed solid particles that are free-flowing and are able to be easily dispersed in an inhalation device and subsequently being inhaled by a human so that the particles reach the lungs for penetration into the alveoli to allow. Therefore, the powder is called "respirable". Preferably the average particle size is less than about 10 microns (μm) in diameter, with a relatively uniform spherical Shape distribution. More preferably the diameter is less than about 7.5 μm and most preferably less than about 5.0 µm. The usual is the particle size distribution between about 0.1 μm and about 5 μm in Diameter, in particular about 0.3 microns to about 5 microns.

The term "dry" means the composition has a moisture content so that the particles easily in an inhalation device are dispersible to an aerosol to build. This moisture content is generally below about 10% by weight (% by weight) of water, usually below about 5% by weight and preferably less than about 3% by weight.

The term "therapeutically effective amount" is the amount that is present in the composition that is required to produce the desired amount To provide medicinal products to the person to be treated, to give the expected physiological response. This amount is for each drug is determined on a case-by-case basis. Guidelines are given below.

The term "physiologically effective amount" is the amount which is fed to a human being to the one you want palliative or curative effect. This amount is specific for each Medicines and their ultimately proven dose content. Guidelines are given below.

The term "pharmaceutically acceptable carrier" means that the carrier is in the Lungs can be ingested without significantly adverse toxicological effects Effects on the lungs.

PROCEDURE AND COMPOSITIONS THE INVENTION

One aspect of this invention is a method of making a spray-dried, drug-based, dispersible, dry powder composition for pulmonary administration, the composition comprising: a therapeutically effective amount of a macromolecule and a pharmaceutically acceptable carrier selected from the group consisting of (i) human Serum albumin, (ii) carbohydrates selected from the group consisting of monosaccharides, disaccharides, cyclodextrins, maltodextrins, raffinose and alditols, (iii) amino acids and (iv) polypeptides, the method comprising:
Providing an aqueous mixture of the macromolecule and the pharmaceutically acceptable carrier and
Spray drying the mixture under conditions that are effective to produce a respirable dry powder, provided that the molecule is neither insulin nor an interferon.

Another aspect of the invention is a dispersible, drug-based dry powder A composition for pulmonary administration obtainable by the above method, the composition comprising a therapeutically effective amount of drug in combination with a pharmaceutically acceptable carrier.

Generally the compositions are of this invention suitable for pulmonary administration their dispersibility characteristics. Such compositions were not previously known in the prior art. When dry the drug may have a crystalline or amorphous form. Some examples of drug compositions used for formulation in dispersible dry powders are shown in Table 1 listed. These include macromolecule-based drugs, with interleukin-1 receptor, Parathyroid hormone (PTH-34), α-1-antitrypsin, Calcitonins, low molecular weight heparin, heparin and nucleic acids are preferred.

A therapeutically effective amount active drug is dependent on the composition of biological activity of the drug used and the required amount in one Unit dosage form vary. Because the present compounds are dispersible , it is very preferred that they be in unit dosage form be produced in a way that is easy to change by the wording and allowed the consumer. This generally means that a Unit dose between about 0.5 mg and 15 mg of total material in the Dry powder composition, preferably between about 2 mg and 10 mg will be. Generally, the amount of medicine in the Composition vary from about 0.05% to about 99.0% by weight. Most preferably the composition will be from about 0.2% to about 97.0% by weight % By weight of drug.

The amount of the pharmaceutically acceptable carrier is the amount required to achieve the necessary stability, dispersibility, Consistency and mass characteristics provide an even pulmonary Ensure administration of the composition to a person who needs it. Numerically, the amount can range from about 0.05 wt% to about 99.95 wt% be dependent from the activity of the drug to be used. Preferably about 5% by weight up to about 95% by weight.

The carrier can be one or a combination be from two or more pharmaceutical drug carriers, however, will generally be essentially free of "penetration enhancers". Are penetration enhancers surfactants Compounds that penetrate a drug through a mucosal membrane or promote lining and are for use in intranasal, intrarectal and intravaginal Drug formulations suggested. Exemplary penetration enhancers include Bile salts, e.g. B. taurocholate, glycocholate and deoxycholate; fusidates, z. B. Taurodehydrofusidate; and biocompatible detergents, e.g. B. Tweene, Laureth-9 and the like. The use of penetration enhancers in Wording for however, the lungs are generally not desirable because the epithelial Blood barrier in the lungs through such surface-active Connections impaired can be. The dry powder compositions of the present Invention are easily absorbed in the lungs without the need penetration enhancers to use.

The types of pharmaceutical drug carriers that as a carrier useful in this invention include stabilizers, such as human serum albumin (HSA), bulking agents, such as carbohydrates, amino acids and polypeptides; pH adjusters or buffers; Salts, such as Sodium chloride; and the like. These carriers can be in a crystalline or can be or can be amorphous be a mixture of the two.

It has been found that HSA particularly valuable as a carrier is because it provides improved dispersibility.

Bulk means that are particularly valuable are compatible carbohydrates, polypeptides, amino acids or Combinations of these. Suitable carbohydrates include monosaccharides, such as galactose, D-mannose, sorbose and the like; Disaccharides like such as lactose, trehalose and the like; Cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin; and polysaccharides such as raffinose, maltodextrins, dextrans and the like; Alditols such as mannitol, xylitol and the like. A preferred one Group of carbohydrates includes lactose, trehalose, raffinose, Maltodextrins and mannitol. Suitable polypeptides include aspartame. Include amino acids Alanine and glycine, with glycine being preferred.

Additives, which are subordinate components of the composition of this invention may be included for conformational stability during the spray drying and to improve the dispersibility of the powder. These additives include hydrophobic amino acids such as tryptophan, tyrosine, leucine, phenylalanine and the like.

Suitable pH adjusters or buffers include organic salts made from organic acids and bases such as sodium citrate, sodium ascorbate and the like; sodium citrate is preferred.

The unit dosage form, the treatment method and the method for producing this invention are hereinafter described described.

Unit dose form

Another aspect of this invention is a unit dosage form for pulmonary administration of dispersible, drug-based dry powder compositions, wherein the dosage form comprises a unit dose receptacle containing one Drug-based powdered drug composition, the composition a therapeutically effective amount of a drug in combination with a pharmaceutically acceptable carrier includes.

In this regard, in accordance with the invention, the composition of this invention (as discussed hereinabove) is incorporated within an appropriate dose receptacle in an amount sufficient to provide a human with unit dose treatment medicament. The dose receptacle is one that fits into a suitable inhalation device to allow aerosolization of the drug-based dry powder composition by dispersion in a gas stream to form an aerosol and then capture of the aerosol so produced in a chamber having a mouthpiece for subsequent inhalation by a person in need of treatment. Such a dose receptacle includes any receptacle that holds the composition known in the art, such as gelatin or plastic capsules with a removable portion that allows a gas stream (e.g., air) to be directed into the receptacle, to disperse the dry powder composition. Such containers are exemplified by those described in U.S. Patents 4,227,522 issued October 14, 1980; 4,192,304, issued March 11, 1980; and 4,105,027, published August 8, 1978. Suitable containers also include those used in conjunction with the Glaxo's Ventolin Rotohaler branded powder inhaler or the Fison's Spinhaler branded powder inhaler. Another unit dose container that provides a superior moisture barrier is formed from an aluminum foil plastic laminate. The drug-based powder is filled into the recess of the moldable film in terms of weight or volume and hermetically sealed with a coating film plastic laminate. Such a container for use with a powder inhalation device is described in US Patent 4,778,054 and with Glaxo's Diskhaler ^® (US patents 4,627,432; 4,811,731; and 5,035,237).

Medicines for treatment a disease state

The dry powders of the invention are appropriate medication to treat a condition related to treatment by responding to a drug in question, the treatment pulmonary administration to a person who needs it, one physiologically effective amount of a dispersible dry powder composition drug-based which is a therapeutically effective Amount of a drug in combination with a pharmaceutical acceptable carrier includes.

The states caused by these compositions can be treated are described in Table 1.

The physiologically effective amount which is required to have a particular condition or a particular Treating the disease state will depend on the individual Condition, duration of treatment, course of treatment, type of drug and other factors, however, can be determined by those skilled in medical technology can be easily determined.

It is currently believed that the effective absorption of a dry powder composition according to the present Invention by a host from a rapid dissolution in the ultra thin (<0.1 (m)) fluid layer the alveolar lining of the lungs. The particles of the present Invention accordingly have a medium Size that is 10 to 50 times larger than the lung fluid layer, making it unexpected that the Particles dissolved become and the drug systemically in a quick way absorbed either local lung or systemic treatment become. Agreement however, the exact mechanism is not required to perform the present invention described herein.

The aerolized dry powder on Drug bases of this invention are particularly suitable instead parenteral administration. Hence the procedure and compositions of the present invention are particularly valuable for chronic treatment protocols in which a patient is himself can medicate. The patient can inhale a desired dose an appropriate amount of medication as just described. The effectiveness of systemic delivery via the procedure as just is typically described in the range of about 15% to 50% his.

Aerolization process of the powder

Yet another aspect of this invention is an apparatus and method for aerolizing a drug-based dry powder composition comprising a therapeutically effective amount of drug in combination with a pharmaceutically acceptable carrier, the method dispersing an amount of the dry powder composition in a gas stream to form an aerosol and trapping the aerosol in a chamber with a mouthpiece for subsequent inhalation by a patient.

Another detailed description this process is described in pending US patent application serial no. 07 / 910,048 and 08 / 207,472 found.

Preparation of the compositions

Another aspect of this invention is a method of making a dry powder composition on the pharmaceutical basis of this invention comprising spray drying an aqueous Mixture of the drug and a pharmaceutically acceptable support under conditions to make a respirable dry powder composition provide.

Spray drying is a process wherein a homogeneous aqueous Mixture of medication and the carrier via a nozzle (e.g. a two-fluid nozzle), fast rotating Disc or an equivalent Device into a hot Gas stream is introduced to atomize the solution fine droplets to build. The watery Mixture can be a solution Suspension, slurry or the like. However, it must be homogeneous to ensure even distribution of the components in the mixture and ultimately the powdered composition sure. The aqueous mixture is preferably a solution. The Solvent, generally water, quickly evaporates from the droplets, producing a fine dry powder containing particles of 1 up to 5 μm Has diameter. Surprisingly The drug did not decompose when exposed to the hot drying gas exposed and the resulting drug-containing spray-dried Powder can are manufactured to be of sufficient purity for pharmaceutical Have application. Acceptable purity is defined as less than 5% decomposition products and contaminants, preferably less than 3% and most preferably less than 1%.

Spray drying is done under conditions carried out, to an essentially amorphous powder with a homogeneous structure to lead, that a particle size that is respectable, a low moisture content and flow characteristics which allow easy aerosolization. Preferably the particle size of the resulting Powder such that more than about 98% of the mass is in particles, which have a diameter of about 10 μm or less, wherein about 90% of the mass is in particles that are less in diameter than 5 μm exhibit. Alternatively, about 95% of the mass will be particles with a diameter of less than 10 μm have, with about 80% of the mass of the particles having a diameter of less than 5 μm exhibit.

The solutions can then be in a conventional Spray drying equipment from commercial providers such as Buchi, Niro, Yamato Chemical Co., Okawara Kakoki Co., and the like can be dried, resulting in an im Essentially amorphous particulate Product leads.

For the spraying process can such spraying methods are used like rotary atomization, pressure atomization and Two-Fluidzerstäuben. Examples of the devices used in these processes include "Parubisu [Phonetic rendering] Mini-Spray GA-32 "and" Parubisu Spray Drier DL-41 "manufactured by Yamato Chemical Co. Or "Spray Drier CL-8 "," Spray Drier L-8 "," Spray Drier FL-12 "," Spray Drier FL-16 "or" Spray Drier FL-20 ", manufactured by Okawara Kakoki Co., which for the method of spraying using an atomizer can be used with a rapidly rotating disc.

Although no special restrictions on the nozzle of the atomizer used for spraying in the present method, it is necessary to use a nozzle to use which is a spray dried Composition with a grain diameter generated that is suitable for nasal, pharyngeal or pulmonary Administration. For example, you can the nozzle types "1A", "1", "2A", "2", "3" and the like by Yamato Chemical Co., for the above-mentioned spray dryer used, which is manufactured by the same company. In addition, the Disc types "MC-50", "MC-65" or "MC-85" manufactured by Okawara Kakoki Co., as rotating disks of the spray dryer atomizer manufactured by the same company.

Although no special restrictions on the gas used to dry the sprayed material air, nitrogen gas or an inert gas is recommended use. The temperature of the inlet of the gas used Drying the sprayed Materials is such that there is no heat deactivation of the sprayed material causes. The temperature range can be between about 50 ° C to about 200 ° C, preferably between about 50 ° C and 100 ° C vary. The temperature of the inlet gas used to dry the sprayed Material used can be between about 0 ° C and about 150 ° C, preferably between 0 ° C and 90 ° C and even more preferably vary between 0 ° C and 60 ° C. The fact that Inlet and outlet temperatures above about 55 ° C can be used surprising in terms of the fact that most macromolecule-based drugs at this temperature be deactivated, with almost complete deactivation at about 70 ° C occurs.

The drug-based dispersible dry powders of the present invention may be optional can be combined with pharmaceutical carriers or auxiliaries which are suitable for respiratory and pulmonary administration. Such carriers can simply serve as bulk agents when it is desired to reduce the drug concentration in the powder to be delivered to a patient, but can also serve to improve the stability of the drug compositions and improve the dispersibility of the powder within a powder disperser to make it more efficient to provide reproducible delivery of the drug and to improve handling characteristics of the drug, such as flowability and consistency, to facilitate manufacture and powder filling.

Such carrier materials can with the medicine before spray drying be united, d. H. by adding the carrier material to the cleaned one Bulk solution. In this way, the carrier particles formed simultaneously with the drug particles to form a homogeneous To produce powder. Alternatively, you can the carrier be made separately in a powder form and with the dry Drug powder can be combined by mixing. The powder carriers are usually may be crystalline (to avoid water absorption) in some cases be amorphous or mixtures of crystalline and amorphous. The size of the carrier particles can be selected become fluidity to improve the drug powder, typically in the range of 25 μm up to 100 μm is. A preferred carrier material is crystalline lactose with a size in the range given above.

Some of the following macromolecular drugs and examples are only for Comparative purposes are included and do not fall within the scope of claims.

Table 1 SELECTED MACROMOLECULAR PRODUCTS FOR SYSTEMIC APPLICATION

Table 1 - continued

Table 1 - continued

The following examples are provided for illustration and are not intended to be limiting.

EXPERIMENTAL

According to the subject of the present Invention, were the following dispersible dry powder formulations manufactured as described. All compositions made according to the present Fulfill invention the strict specifications for Content and purity that for pharmaceutical products are required.

EXAMPLE I

20.0% INSULIN FORMULATION FOR PULMONAL ADMINISTRATION

A. Formulation

A crystalline amount of human zinc insulin was obtained from Eli Lilly and Company, Indianapolis, IN. A 20% insulin formulation was achieved by combining 1.5 mg insulin per 1.0 ml deionized water with 4.96 mg / ml USP mannitol and 1.04 mg / ml citrate buffer (sodium citrate dihydrate USP and citric acid monohydrate USP) for a total solid concentration of 7.5 mg / ml at pH of 6.7 ± 0.3.

B. Spray drying

A dry powder of the 20% insulin formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions: Temperature of the aqueous mixture 2-8 ° C inlet temperature 120-122 ° C feed rate 5.3 ml / min outlet 80-81 ° C

When the aqueous mixture was used up the outlet temperature at <80 ° C for about 10 Minutes by slowly lowering the inlet temperatures, around a secondary Provide drying.

C. Characterization

The above 20% insulin dry powder composition contained 66.1 mannitol and 13.9% citrate. It was found that the composition 1.1 to 2.0% moisture according to measurement by a coulometric Karl Fischer method, using of a Mitsubishi CA-06 moisture meter.

The particle size distribution of the composition was by liquid centrifugal sedimentation in a Horiba CAPA-700 particle size analyzer following dispersion of the powder on a Sedisperse A-11 (Micrometrics, Norcross, GA) was measured and was determined as 1.3 μm to 1.5 μm MMD.

The dose of insulin powder composition delivered was measured by collecting the aerosol powder by a Dry powder dispersion device was produced, which are similar devices is that in the pending US Anmeldungsseriennrn. 07 / 910.048; 08 / 313.707; 08 / 309,691 and PCT / US92 / 05621 on a filter placed over the mouthpiece of the device is arranged. The fed Dose of the insulin powder composition was found to be 563 ± 16 μg or 60 up to 64% of the total powder (5.0 mg) introduced into the device was decided.

The aerosol particle size distribution, measured using a cascade impactor (California Measurements IMPAQ-6) was determined as 2.0 μm MMAD, with 86% to 90% of the particles <5.0 μm in diameter exhibited.

The insulin content of the powder, measured by reverse phase HPLC (rpHPLC) as 197 µg / mg powder determines what 99% of the expected insulin speaks. There were no decomposition signals detected in the chromatogram.

EXAMPLE II

5.0% parathyroid hormone formulation FOR PULMONAL ADMINISTRATION

A. Formulation

A 34 amino acid active fragment set of the thyroid hormone PTH (1-34) was obtained from BACHEM CALIFORNIA, Torrance, CA. A 5.0% PTH (1-34) formulation was obtained by pooling from 0.375 mg PTH (1-34) per 1.0 ml deionized water with 6.06 mg / ml mannitol USP and 1.04 mg / ml citrate buffer (sodium citrate dihydrate USP and citric acid monohydrate USP) for a total solids concentration of 7.48 mg / ml at pH of 6.3.

B. Spray drying

A dry powder of the 5.0% PTH (1-34) formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions: Temperature of the aqueous mixture 2-8 ° C inlet temperature 122-124 ° C feed rate 5.2 ml / min outlet 73-74 ° C

When the aqueous mixture was used up the outlet temperature at <80 ° C for about 5 Minutes by slowly lowering the inlet temperature, around a secondary Provide drying.

C. Characterization

The following characterization of the Dry powder formulation described above was used the procedures given in Example 1, unless otherwise specified.

The above 5.0% PTH (1-34) dry powder composition contained 81.0% mannitol and 13.9% citrate. The wording contained 0.5% moisture.

The particle size distribution of the composition was considered to be 2.4 μm and 2.7 µm MMD determined in separate measurements.

The dose of PTH (1-34) powder delivered was found to be 161 μg or 64.5% and 175 μg or 69.2% determined in separate measurements.

The PTH (1-34) content of the powder, measured by rpHPLC, was determined as 48.5 μg / mg powder, which is 97% of the expected value. No decomposition signals were made detected in the chromatogram.

EXAMPLE III

0.7% INTERLEUKIN-1 RECEPTOR FORMULATION FOR PULMONAL ADMINISTRATION

A. Formulation

A total amount of interleukin-1 receptor, IL-1 receptor, was developed by Immunex Corporation, Seattle, WA. receive. A 0.7% IL-1 receptor formulation was obtained by pooling 0.053 mg IL-1 receptor per 1.0 ml deionized water with 7.07 mg / ml raffinose (Pfanstiehl, Waukegan, IL) and 0.373 mg / ml Tris buffer at a pH of 7.18.

B. Spray drying

A dry powder of the 0.7% IL-1 receptor formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions: Temperature of the aqueous mixture 2-8 ° C inlet temperature 135-137 ° C feed rate 4.9 ml / min outlet 92-93 ° C

When the aqueous mixture was used up the outlet temperature was slow at 90 ° C for about 15 minutes Lowering the inlet temperature held to secondary drying provided.

C. Characterization

The following characterization of the Dry powder formulation described above was used the procedure described in Example 1 unless otherwise stated.

The above 0.7% IL-1 receptor dry powder composition contained 94.3 raffinose and 5.0% tris. The wording contained 1.84 ± 0.25 Humidity.

The particle size distribution of the composition was found to be 1.95 μm MMD determined, with 100% of the particles having <5.0 μm.

The dose of IL-1 receptor powder delivered was found to be 22.3 ± 2.0 μg or 53.4 ± 4.7% certainly.

The aerosol particle size distribution was found to be 3.2 μm MMAD determined, with 77 of the particles being <5.0 μm in diameter.

The IL-1 receptor content of the powder, according to measurement by rpHPLC, was found to be 8.4 µg / mg determines what 120% of the expected IL-1 receptor speaks. In the chromatogram no decomposition signals were detected.

EXAMPLE IV

5.0% INTERLEUKIN-1 RECEPTOR FORMULATION FOR PULMONAL ADMINISTRATION

A. Formulation

A total amount of interleukin-1 receptor, IL-1 receptor, was developed by Immunex Corporation, Seattle, WA. receive. A 5.0% IL-1 receptor formulation was obtained by pooling 0.375 mg IL-1 receptor per 1.0 ml deionized water with 6.77 mg / ml raffinose and 0.351 mg / ml Tris buffer at pH 7.35.

B. Spray drying

A dry powder of the 5.0% IL-1 receptor formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions Temperature of the aqueous mixture 2-8 ° C inlet temperature 138 ° C feed rate 4.9 ml / min outlet 91 ° C

When the aqueous mixture was used up was the outlet temperature for about 15 minutes at 90 ° C slowly lowering the inlet temperature held to secondary drying provided.

C. Characterization

The following characterization of the Dry powder formulation described above was used the procedure described in Example 1 unless otherwise stated.

The above 5.0% IL-1 receptor dry powder composition contained 90.3 raffinose and 4.7% tris. The wording contained 1.75 ± 0.26 moisture.

The particle size distribution of the composition was found to be 2.74 µm MMD determined, with 97% of the particles having <5.0 μm.

The dose of IL-1 receptor powder delivered was found to be 123.4 ± 24.5 μg or 49.3 ± 9.8% certainly.

The aerosol particle size distribution was considered to be 4.1 μm MMAD determined, with 64% of the particles having a diameter of <5.0 μm.

The IL-1 receptor content of the powder, was measured determined by rpHPLC as 52.7 ± 1.8 μg / mg, what kind of 105% of the expected IL-1 receptor speaks. There were no decomposition signals detected in the chromatogram.

EXAMPLE V

26.7% HUMAN CALCITON INFORMATION FOR PULMONAL ADMINISTRATION

A. Formulation

A total amount of human calcitonin was obtained from Ciba Geigy. A 26.7% human calcitonin formulation was obtained by combining 1.9 mg of human calcitonin per 1.0 ml deionized water with 4.3 mg / ml mannitol and 0.9 mg / ml Citrate buffer at a pH of 3.86.

B. Spray drying

A dry powder from the 26.7% human calcitonin formulation described above was made prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions Temperature of the aqueous mixture 4 ° C inlet temperature 119 ° C feed rate 5.5 ml / min outlet 78 ° C Zerstäuberkühlmitteltemperatur 0-5 ° C Cyclo coolant temperature 25-30 ° C

When the aqueous mixture was used up was the outlet temperature for about 10 minutes at 80 ° C slowly lowering the inlet temperature held to secondary drying provided.

C. Characterization

The following characterization of the dry powder composition described above was used the procedure described in Example 1 unless otherwise stated.

The above 26.7% human calcitonin dry powder composition contained 60% mannitol and 13.3% citrate. The wording contained 0.71% moisture.

The particle size distribution of the composition was determined as 1.33 ± 0.63 μm MMD.

The dose of human calcitonin powder delivered was found to be 76.8 ± 6.7% certainly.

The human calcitonin content of the powder, was measured by rpHPLC as 272.0 µg / mg determines what 102 ± 1.7% of the expected human calcitonin. There were no decomposition signals in demonstrated on the chromatogram.

EXAMPLE VI

90% ALPHA-1 ANTITRYPSINFORMULATION FOR PULMONAL ADMINISTRATION

A. Formulation

A total amount of alpha-1 antitrypsin, A1A, obtained from Armor Pharmaceutical Company, Kankakee, IL. A 90% A1A formulation was obtained by pooling of 4.89 mg A1A per 1.0 ml deionized water at 0.54 mg / ml Citrate buffer at pH 6.0.

B. Spray drying

A dry powder of the 90% A1A formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions Temperature of the aqueous mixture 4 ° C inlet temperature 98-101 ° C feed rate 5.0 ml / min outlet 65 ° C Zerstäuberkühltemperatur 2-8 ° C Cyclo cooling temperature 30 ° C

When the aqueous mixture was used up the outlet temperature was slow at 69 ° C for about 10 minutes Lowering the inlet temperature held to secondary drying provided.

C. Characterization

The following characterization of the Dry powder composition described above was carried out under Use the procedures described in Example 1 unless it is stated differently.

The above 90% A1A dry powder composition contained 10.0% citrate.

The formulation contained 4.79% moisture.

The particle size distribution of the composition was determined as 1.71 ± 0.87 μm MMD.

The dose of 90% A1A powder delivered was as 67.0 ± 5.0% certainly.

The aerosol particle size distribution was determined as 1.0 μm MMAD, with 90% of the particles < Had a diameter of 5.0 μm.

The A1A content of the powder was according to measurement determined by rpHPLC with 80% of the expected value. No decomposition signals were detected in the chromatogram. The activity after spray drying was found to be 74 ± 1% certainly.

EXAMPLE VII

0.3% BETA INTERFERON FORMULATION FOR PULMONAL ADMINISTRATION CONTAINING HUMAN SERUM ALBUMINE

A. Formulation

A total amount of beta interferon, IFN-β obtained from Toray Industries, Inc., Tokyo, Japan. A 0.3% IFN-β formulation was obtained by combining 0.025 mg IFN-β per 1.0 ml deionized water with 5.54 mg / ml human serum albumin (HSA), 2.3 mg / ml citrate buffer and 0.345 mg / ml NaCl at a pH of 4.5.

B. Spray drying

A dry powder of the 0.3% IFN-β formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions: Temperature of the aqueous mixture 2-8 ° C inlet temperature 93 ° C feed rate 2.7 ml / min outlet 62 ° C

C. Characterization

The following characterization of the Dry powder formulation described above was used of the procedures described in Example I unless otherwise stated.

The above 0.3% IFN-β dry powder composition contained 66.0% HSA, 27.4% citrate, 4.1% NaCl. The wording contained 4.22% moisture.

The particle size distribution of the composition was found to be 1.62 μm MMD determined, with 94.8% of the particles <5 microns exhibited.

The dose of the 0.3% IFN-β powder supplied was found to be 9.9 μg / mg or 66.0 ± 4.0% certainly.

The aerosol particle size distribution was found to be 2.0 μm MMAD determined, with 85% of the particles having a diameter of <5.0 μm.

The IFN-β activity of the powder was determined by IFN-β enzyme immunoassay (Toray-Fuji Bionics) measured and was measured as 109 ± 8% the expected activity certainly.

EXAMPLE VIII

0.3% BETA INTERFERON FORMULATION FOR PULMONAL ADMINISTRATION CONTAINING RAFFINOSE

A. Formulation

A total amount of beta interferon, IFN-β obtained from Toray Industries, Inc., Tokyo, Japan. A 0.3% IFN-β formulation was obtained by combining 0.025 mg IFN-β per 1.0 ml deionized water with 4.7 mg / ml raffinose, 1.0 mg / ml human serum albumin (HSA), 2.3 mg / ml citrate buffer and 0.3 mg / ml NaCl at pH from 4.5.

B. Spray drying

A dry powder of the 0.3% IFN-β formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions: Temperature of the aqueous mixture 2-8 ° C inlet temperature 145 ° C feed rate 5.0 ml / min outlet 87 ° C

When the aqueous mixture was used up the outlet temperature was slow at 97 ° C for about 5 minutes Lowering the inlet temperature held to secondary drying provided.

C. Characterization

The following characterization of the Dry powder formulation described above was used of the procedures described in Example I unless otherwise stated.

The above 0.3% IFN-β dry powder composition contained 56.4 raffinose, 11.9% HSA, 27.4% citrate, 3.5% NaCl. The Formulation contained 0.69 moisture.

The particle size distribution of the composition was found to be 2.06 μm MMD determined, with 88.9% of the particles <5 microns were.

The dose of the 0.3% IFN-β powder supplied was found to be 10.2 μg / mg or 68.0 ± 2.0% certainly.

The aerosol particle size distribution was found to be 2.5 μm MMAD determined, with 84% of the particles having a diameter of <5.0 μm.

The IFN-β activity of the powder was determined according to the IFN-β enzyme immunoassay (Toray-Fuji Bionics) measured and was measured as 109 ± 8% the expected activity measured.

EXAMPLE IX

93% FORMULATION OF LOW MOLECULAR WEIGHT HEPARIN FOR PULMONAL ADMINISTRATION

A. Formulation

A total amount of heparin sodium salt low molecular weight (average molecular weight: about 6000) from pig intestinal mucosa, heparin (LMW) was obtained from Sigma Chemical, St. Louis, MO. A 93% heparin (LMW) formulation was obtained by pooling 6.9 mg heparin (LMW) per 1.0 ml deionized water with 0.5 mg / ml HSA at a pH of 6.9.

B. Spray drying

A dry powder of the 93% heparin (LMW) formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions: Temperature of the aqueous mixture 2-8 ° C inlet temperature 140 ° C feed rate 3.8 ml / min outlet 85 ° C Zerstäuberkühlmitteltemperatur 2-8 ° C Cyclo coolant temperature 20 ° C

When the aqueous mixture was used up the outlet temperature was slow at 80 ° C for about 10 minutes Lowering the inlet temperature held to secondary drying provided.

C. Characterization

The following characterization of the Dry powder formulation described above was carried out at Use the procedures described in Example 1 unless it is stated differently.

The above 93% heparin (LMW) dry powder composition contained 7.0 HSA.

The dose of the 93% heparin (LMW) powder supplied was found to be 60.0 ± 1.0 % certainly.

The aerosol particle size distribution was with 3.5 microns MMAD determined, with 70% of the particles having a diameter of <5.0 μm.

EXAMPLE X

97% UNFRACTED HEPARINE FORMULATION FOR PULMONAL ADMINISTRATION

A. Formulation

A lot of unfractionated total heparin sodium salt from pig intestinal mucosa, heparin was obtained from Sigma Chemical, St. Louis, MO. A 97% heparin formulation was made obtained by combining 7.0 mg of heparin per 1.0 ml of deionized Water with 0.25 mg / ml HSA at a pH of 6.55.

B. Spray drying

A dry powder of the 97% heparin formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions: Temperature of the aqueous mixture 2-8 ° C inlet temperature 150 ° C feed rate 4.0 ml / min outlet 85 ° C Zerstäuberkühlmitteltemperatur 2-8 ° C Cyclo coolant temperature 20 ° C

When the aqueous mixture was used up the outlet temperature was slow at 80 ° C for about 10 minutes Lowering the inlet temperature held to secondary drying provided.

C. Characterization

The following characterization of the Dry powder formulation described above was used performed the procedure described in Example i unless otherwise stated.

The above 97% heparin dry powder composition contained 3.0% HSA. The formulation contained 5.11% moisture.

The particle size distribution of the composition was found to be 2.0 to 2.5 μm MMD determined.

The dose of the 97% heparin powder supplied was measured as 79.0 ± 6.0% certainly.

The aerosol particle size distribution was with 3.2 μm MMAD determined, with 70% of the particles having a diameter of <5.0 μm.

EXAMPLE XI

LIPIDVEKTORGENFORMULIERUNG FOR PULMONAL ADMINISTRATION

A. Formulation

A pCMVβ DNA: lipid vector was obtained from from Genzyme Corporation, Cambridge, MA. A 0.71% DNA: Lipid vector formulation was obtained by pooling 0.005: 0.03 mg DNA lipid vector per 1.0 ml deionized water with 5.3 mg / ml glycine (J. T. Baker), 0.3 mg / ml HSA at pH of 6.4.

B. Spray drying

The dry powder of the DNA: lipid vector formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions: Temperature of the aqueous mixture 2-8 ° C inlet temperature 120 ° C feed rate 3.8 ml / min outlet 71 ° C Zerstäuberkühlmitteltemperatur 2-8 ° C Cyclo coolant temperature 2-8 ° C

When the aqueous mixture was used up the outlet temperature was slow at 65 ° C for about 5 minutes cooling down inlet temperature is maintained to provide secondary drying.

C. Characterization

The following characterization of the Dry powder formulation described above was used performed the procedure described in Example i unless otherwise stated.

The above 0.71% DNA: lipid vector dry powder composition contained 93.97% glycine and 5.32% HSA.

The particle size distribution of the composition was found to be 2.0 μm MMD determined.

The dose administered 97% heparin (HMW) powder was found to be 64.0 ± 1.0 certainly.

The aerosol particle size distribution was considered to be 2.4 μm MMAD determined, with 75% of the particles having a diameter of <5.0 μm.

The activity after spray drying was determined as 160% of the expected value.

EXAMPLE XII

ADENOVIRUSVEKTORGENFORMULIERUNG FOR PULMONAL ADMINISTRATION

A. Formulation

A lot of pCMVβ DNA: adenovirus vector was generated obtained from Genzyme Corporation, Cambridge, MA. A DNA: Adenovirus vector formulation was obtained by combining 108 PFU / ml DNA: lipid vector per 1.0 ml of deionized water with 6.1 mg / ml glycine (J. T. Baker), 2.5 mg / ml HSA, 1.9 mg / ml phosphate buffer, at a pH of 7.4.

B. Spray drying

A dry powder from the DNA: lipid vector formulation described above was prepared by spray drying the aqueous mixture using a Buchi laboratory spray dryer under the following conditions: Temperature of the aqueous mixture 2-8 ° C inlet temperature 105 ° C feed rate 2.9 ml / min outlet 72 ° C Zerstäuberkühlmitteltemperatur 2-8 ° C Cyclo coolant temperature 20 ° C

When the aqueous mixture was used up the outlet temperature was slow at 70 ° C for about 10 minutes Lowering the inlet temperature held to secondary drying provided.

C. Characterization

The following characterization of the Dry powder formulation described above was carried out at Use the procedures described in Example i, unless it is stated differently.

The above DNA adenovirus vector dry powder composition contained 58 glycine and 24% HSA and 18% phosphate buffer.

The particle size distribution of the composition was found to be 2.3 μm MMD determined.

The dose of 97% heparin (HMW) powder delivered was found to be 51.0 ± 1.0 % certainly.

The aerosol particle size distribution was with 1.8 μm MMAD determined, with 80% of the particles having a diameter of <5.0 μm.

The activity after spray drying was found to be 76% of the expected value.

Claims (31)

Process for making a spray dried, drug-based, dispersible dry powder composition for pulmonary administration, the composition being a therapeutic effective amount of a macromolecule and a pharmaceutically acceptable one carrier includes selected from the group consisting of (i) human serum albumin, (ii) carbohydrates, selected from the group consisting of monosaccharides, disaccharides, cyclodextrins, Maltodextrins, raffinose and alditols, (iii) amino acids and (iv) polypeptides, the method comprising: Provide an aqueous Mixture of the macromolecule and the pharmaceutically acceptable Carrier and spray drying of the mixture under conditions that are effective to achieve a respirables Manufacture dry powder, on the condition that the molecule is neither Insulin is still an interferon. The method of claim 1, wherein the macromolecule is selected from the group consisting of calcitonins, erythropoietin, factor IX, G-CSF, GM-CSF, growth hormone, heparin, low molecular weight heparin, Interleukin-2, LHRH, Somatostatin analog, vasopressin analog, amylin, ciliary neurotrophic Factor, interleukin-3, interleukin-4, M-CSF, nerve growth factor, parathyroid hormone, thymosin alpha-1, IIb / IIIa inhibitor, alpha-1 Antittrypsin, anti-RSV antibodies, CFTR gene, DNase, BPI protein, anti-CMV antibody, interleukin-1 receptor and nucleic acids. The method of claim 1 or 2, wherein the aqueous mixture of the macromolecule and the wearer homogeneous mixture. The method of claim 3, wherein the aqueous mixture of the macromolecule and the carrier a solution is. A method according to any one of claims 1 to 4, wherein the respirable Dry powder used in the spray drying step is produced, comprises individual particles, wherein the carrier and the macromolecule mixed evenly are. A method according to any one of claims 1 to 5, wherein the respirable Dry powder used in the spray drying step is produced when administered pulmonarily to a patient, who needs one rapid systemic absorption of the macromolecule allowed. A method according to any one of claims 1 to 6, wherein the carrier is substantially free of penetration enhancers is. A method according to claim 1 or claim 2, wherein the carrier selected is selected from the group consisting of galactose, D-mannose, sorbose, Lactose, trehalose, 2-hydroxypropyl-β-cyclodextrin, raffinose, mannitol and xylitol. A method according to claim 1 or claim 2, wherein the carrier an amino acid is. A method according to any one of claims 1 to 9, wherein the composition still a hydrophobic amino acid includes. The method of claim 10, wherein the hydrophobic amino acid selected is from the group consisting of tryptophan, thyrosine, leucine and phenylalanine. The method of claim 2, wherein the macromolecule is selected from the group consisting of interleukin-1 receptor, parathyroides Hormone, alpha-1 antitrypsin, low molecular weight heparin and Nucleic acids. spray-dried, drug-based, dispersible composition for pulmonary administration comprising: a therapeutically effective Amount of a macromolecule and a pharmaceutically acceptable one Carrier, being the composition by the method according to any one of claims 1 to 12 available is. A dry powder composition according to claim 13 comprising Particles that have an even distribution of macromolecule and carrier exhibit. Dry powder composition according to claim 13 or Claim 14, wherein 95% of the mass of the composition comprises particles a particle size below Include 10 microns. Dry powder composition according to any one of claims 13 to 15, comprising particles ranging in size from 1.0-5.0 microns medium mass diameter (MMD). Dry powder composition according to any one of claims 13 to 16, comprising particles ranging in size from 1.0 to 4.0 microns medium mass diameter (MMD). Dry powder composition according to any one of claims 13 to 17, comprising particles with an aerosol particle size in the range from 1.0 - 5.0 Micrometer average aerodynamic mass diameter (MMAD). Dry powder composition according to any one of claims 13 to 18, comprising particles with an aerosol particle size in the range from 1.0 - 4.0 Micrometer average aerodynamic mass diameter (MMAD). Dry powder composition according to any one of claims 13 to 19, characterized in that the dose administered is greater than Is 30%. Dry powder composition according to any one of claims 13 to 20, characterized in that the dose administered is greater than Is 60%. Dry powder composition according to any one of claims 13 to 21, with a homogeneous structure. Dry powder composition according to any one of claims 13 to 22, comprising less than 5% degradation products. Dry powder composition according to any one of claims 13 to 23, which changes rapidly with pulmonary administration to an individual in the fluid layer of the alveolar lining of the lungs. A composition according to any one of claims 13 to 24 with a moisture content below 10% by weight. Dry powder composition according to any one of claims 13 to 25 wherein the macromolecule is rapidly systemically absorbed when administered by inhalation. Dry powder composition according to any one of claims 13 to 26, comprising particles less than 10 in diameter Micrometers. Dry powder composition according to any one of claims 13 to 27, wherein the macromolecule a nucleic acid is. Aerosolized dry powder composition after one of the claims 13 to 28. Dosage unit form for the pulmonary administration of a Macromolecule-based composition comprising a unit dose recipient containing the dry powder composition according to one of the claims 13 to 28. Process for aerosolizing a dry powder composition which is based on a drug, including a therapeutic effective amount of a drug based on a macromolecule in combination with a pharmaceutically acceptable carrier, the method comprising: dispersing an amount of a dry powder composition according to any one of claims 13 to 28 in a gas stream to form an aerosol and Include the Aerosols in a suitable chamber for subsequent inhalation of the Aerosols by a patient.